Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia

被引：51

作者：

Banerjee, A. ^{[1
]}

Wang, H-Y ^{[2
]}

Borgmann-Winter, Ke ^{[1
]}

MacDonald, M. L. ^{[1
]}

Kaprielian, H. ^{[1
]}

Stucky, A. ^{[2
]}

Kvasic, J. ^{[2
]}

Egbujo, C. ^{[1
]}

Ray, R. ^{[1
]}

Talbot, K. ^{[1
]}

Hemby, S. E. ^{[3
]}

Siegel, S. J. ^{[1
]}

Arnold, S. E. ^{[1
]}

Sleiman, P. ^{[4
,5
]}

Chang, X. ^{[4
,5
]}

Hakonarson, H. ^{[4
,5
]}

Gur, R. E. ^{[1
]}

Hahn, C-G ^{[1
]}

机构：

[1] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[2] CUNY, Sch Med, Dept Physiol Pharmacol & Neurosci, New York, NY 10031 USA

[3] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27103 USA

[4] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

来源：

MOLECULAR PSYCHIATRY | 2015年 / 20卷 / 09期

关键词：

RECEPTOR HYPOFUNCTION; POSTSYNAPTIC DENSITY; SYNAPTIC PLASTICITY; PREFRONTAL CORTEX; MESSENGER-RNA; EXPRESSION; GLUTAMATE; BRAIN; MECHANISMS; GENE;

D O I：

10.1038/mp.2014.115

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-alpha (RPTP alpha) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations.

引用

页码：1091 / 1100

页数：10

共 65 条

[31] SUBANESTHETIC EFFECTS OF THE NONCOMPETITIVE NMDA ANTAGONIST, KETAMINE, IN HUMANS - PSYCHOTOMIMETIC, PERCEPTUAL, COGNITIVE, AND NEUROENDOCRINE RESPONSES [J].